Process of making chalcone derivatives

• US 20040181075A1
• Filed: 12/19/2003
• Published: 09/16/2004
• Est. Priority Date: 12/19/2002
• Status: Abandoned Application

• Current Assignee: General Electric Company
• Original Assignee: General Electric Company
• Inventors: Weingarten, M. David, Meng, Charles Q., Sikorski, James A., Ni, Liming, Worsencroft, Kimberly J.
• Application Number:
  US10/741,283
• Publication Number:
  US 20040181075A1
• Time in Patent Office: Days
• US Class Current: 548/253
• CPC Class Codes: C07D 207/337 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/50 Ketonic radicals
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 241/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 277/30 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 307/28 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/80 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 333/22 Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/56 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 333/60 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

This invention is a novel methods of manufacturing chalcones that includes reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde with an acetophenone in a solvent or mixture of solvents in the presence of LiOMe. Also provided are new chalcones for the treatment of medical conditions.

Claims

1. A process of manufacturing a chalcone that includes reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde with an acetophenone in a solvent or mixture of solvents in the presence of LiOMe.

2. The process of manufacturing a compound of Formula I or salts thereof of claim 1,

3. The process of claim 1, wherein the chalcone is of formula I,

4. The process of claim 1, wherein the chalcone is of Formula I or a salt thereof

5. The process of claim 4 wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, C(O)OH, C(O)OR², (CH₂)_yC(O)OR¹ wherein y is 1, 2, 3, 4, 5, or 6, C(R¹)₂C(O)OR¹;

wherein at least one of R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

must be selected from the group consisting of C(O)OH, C(O)OR², (CH₂)_yC(O)OR¹ wherein y is 1, 2, 3, 4, 5, or 6, C(R¹)₂C(O)OR¹;

R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

are independently selected from the group consisting of hydrogen, halo, alkoxy, alkoxy alkoxy alkoxy, amino, NR⁷R⁸, heteroaryloxy, heterocyclic, and heteroaryl, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heteroaryl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, oxo, cyano, carboxy, carboxyalkyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, —

C(O)NR⁷R⁸, —

C(O)NH₂, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 7-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein R⁷ and R⁸ can be optionally substituted with one or more selected from the group consisting of alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

wherein at least one of R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

must be an optionally substituted carbon-carbon linked heterocyclic or heteroaryl;

comprising;

reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde of Formula II

with an acetophenone of Formula III

wherein R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

for Formula II and III are as defined above;

in a solvent or mixture of solvents in the presence of LiOMe.

6. The process of claim 5 wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, C(O)OH, and C(O)OR²;

wherein at least one of R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

must be selected from the group consisting of C(O)OH and C(O)OR²;

R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

are independently selected from the group consisting of hydrogen, halo, alkoxy, alkoxy, heteroaryloxy, heterocyclic, and heteroaryl, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heteroaryl, heterocyclic, alkoxy, oxo, carboxy, carboxyalkyl, alkoxycarbonyl, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, and heteroarylalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, heterocyclic, alkoxy, oxo, —

C(O)NH₂, and —

C(O)N(R²)₂;

wherein at least one of R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

must be an optionally substituted carbon-carbon linked heterocyclic or heteroaryl;

comprising;

reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde of Formula II

with an acetophenone of Formula III

wherein R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

for Formula II and III are as defined above;

in a solvent or mixture of solvents in the presence of LiOMe.

7. The process of claim 6 wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen and C(O)OH;

wherein at least one of R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

must be C(O)OH;

R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

are independently selected from the group consisting of hydrogen, halo, alkoxy, alkoxy, heterocyclic, and heteroaryl, all of which can be optionally substituted by one or more selected from the group consisting of lower alkyl, hydroxy, hydroxyalkyl, heteroaryl, heterocyclic, alkoxy, alkoxycarbonyl, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, arylalkyl, and heteroarylalkyl, wherein all may be substituted by one or more selected from the group consisting of lower alkyl, heterocyclic, alkoxy, —

C(O)NH₂, and —

C(O)N(R²)₂;

wherein at least one of R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

must be an optionally substituted carbon-carbon linked heterocyclic or heteroaryl;

comprising;

reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde of Formula II

with an acetophenone of Formula III

wherein R^2α

, R^3α

, R^4α

R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

for Formula II and III are as defined above;

in a solvent or mixture of solvents in the presence of LiOMe.

8. The process of claim 4 wherein the compound to be manufactured is selected from the group consisting of

4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid;

4-{3E-[4-(1-Carboxy-1-methyl-ethoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

4-[(2E)-3-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid;

4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-[3E-(2,6-Dimethoxy-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-{3E-[2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-phenyl]-acryloyl}-benzoic acid;

4-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-[3E-(3-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

3-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-[3E-(3-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid;

4-[3E-(2-Methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-[3E-(2,4-Dimethoxy-5-pyrazin-2-yl-phenyl)-acryloyl]-benzoic acid;

4-(3E-{2-Methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid;

4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic acid methyl ester;

4-[3E-(4-Ethoxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-[3E-(4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-[3E-(2,4-Dimethoxy-5-thiazol-2-yl-phenyl)-acryloyl]-benzoic acid;

2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-pyrrole-1-carboxylic acid tert-butyl ester;

4-[3E-(2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-{3E-[2-(1-Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;

4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;

4-{3E-[2-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

4-[3E-(2-Pyrrolidin-1-yl-S-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

4-{3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;

4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;

4-[3E-(2-Dimethylcarbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-[3E-(4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-{3E-[2,4-Dimethoxy-5-(2-methyl-thiazol-4-yl)-phenyl]-acryloyl}-benzoic acid;

4-{3E-[5-(1H-Benzoimidazol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;

4-[3E-(2-Carbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;

4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

4-(3E-{4-Methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid, hydrochloride;

4-{3E-[2,4-Dimethoxy-5-(1H-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic acid;

4-{3E-[2,4-Dimethoxy-5-(2H-tetrazol-5-yl)-phenyl]-acryloyl}-benzoic acid;

4-{3E-[5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;

4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzoic acid;

4-[(2E)-3-(5-Benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid;

4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid, hydrochloride; and

4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid.

9. The process of claim 1, wherein the chalcone is of Formula I or a salt thereof

10. The process of claim 9 wherein

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, —

SO₂NH₂, —

SO₂NHR², —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸;

wherein at least one of R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

must be selected from the group consisting of —

SO₂NH₂, —

SO₂NHR², —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, and —

SO₂NHC(O)NR⁷R⁸;

R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

are independently selected from the group consisting of hydrogen, halo, alkoxy, alkoxy alkoxy alkoxy, amino, NR⁷R⁸, heteroaryloxy, heterocyclic, and heteroaryl, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heteroaryl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, —

C(O)NR⁷R⁸, —

C(O)NH₂ and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 7-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein R⁷ and R⁸ can be optionally substituted with one or more selected from the group consisting of alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

wherein at least one of R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

must be an optionally substituted carbon-carbon linked heterocyclic or heteroaryl;

comprising;

reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde of Formula II

with an acetophenone of Formula III

wherein R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

for Formula II and III are as defined above;

in a solvent or mixture of solvents in the presence of LiOMe.

11. The process claim 10 wherein

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, —

SO₂NH₂, —

SO₂NHR², —

SO₂N(R²)₂, and SO₂NR⁷R⁸;

wherein at least one of R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

must be selected from the group consisting of —

SO₂NH₂, —

SO₂NHR², —

SO₂N(R²)₂, SO₂NR⁷R⁸, and —

SO₂NHC(O)R²;

R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

are independently selected from the group consisting of hydrogen, halo, alkoxy, heteroaryloxy, heterocyclic, and heteroaryl, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heteroaryl, heterocyclic, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, and heteroarylalkyl wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, heterocyclic, alkoxy, oxo, —

C(O)NH₂, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 7-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein R⁷ and R⁸ can be optionally substituted with one or more selected from the group consisting of lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, and cyano;

wherein at least one of R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

must be an optionally substituted carbon-carbon linked heterocyclic or heteroaryl;

comprising;

reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde of Formula II

with an acetophenone of Formula III

wherein R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

for Formula II and III are as defined above;

in a solvent or mixture of solvents in the presence of LiOMe.

12. The process of claim 11 wherein

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen and —

SO₂NH₂;

wherein at least one of R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

must be —

SO₂NH₂;

R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

are independently selected from the group consisting of hydrogen, halo, alkoxy, heterocyclic, and heteroaryl, all of which can be optionally substituted by one or more selected from the group consisting of lower alkyl, hydroxy, hydroxyalkyl, heteroaryl, heterocyclic, alkoxy, cyano, alkoxycarbonyl, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, arylalkyl, and heteroarylalkyl wherein all may be substituted by one or more selected from the group consisting of lower alkyl, heterocyclic, alkoxy, —

C(O)NH₂, and —

C(O)N(R²)₂;

wherein at least one of R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

must be an optionally substituted carbon-carbon linked heterocyclic or heteroaryl;

comprising;

reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde of Formula II

with an acetophenone of Formula III

wherein R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

for Formula II and III are as defined above;

in a solvent or mixture of solvents in the presence of LiOMe.

13. The process of claim 9 wherein the compound is selected from the group consisting of:

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzenesulfonamide;

4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;

2-{5-Methoxy-2-[3-oxo-3-(4-aminosulfonyl-phenyl)-E-propenyl]-4-thiophen-2-yl-phenoxy}-2-methyl-propionic acid;

2-{2,4-Dimethoxy-5-[3-oxo-3-(4-aminosulfonyl-phenyl)-E-propenyl]-phenyl}-indole-1-carboxylic acid tert-butyl ester;

4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[4-Methoxy-2-(1H-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzoic acid;

4-{3-[3E-(2,3-Dihydro-furan-2-yl)-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[5-(2,5-Dihydro-furan-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[4-Methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;

4-[3E-(2,4-Dimethoxy-5-pyridin-3-yl-phenyl)-acryloyl]-benzenesulfonamide;

4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid, hydrochloride;

4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;

4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[2-(1H-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;

4-{3E-[4-Methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide; and

4-{3E-[2-(Benzotriazol-1-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide.

14. The process of claim 1, wherein the chalcone is of Formula I or a salt thereof

15. The process of claim 14 wherein

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHSO₂NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHSO₂R²;

wherein at least one of R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

must be selected from the group consisting of —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHSO₂NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHSO₂R²;

R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

are independently selected from the group consisting of hydrogen, halo, alkoxy, alkoxy alkoxy alkoxy, amino, NR⁷R⁸, heteroaryloxy, heterocyclic, and heteroaryl, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heteroaryl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, —

C(O)NR⁷R⁸, —

C(O)NH₂ and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 7-membered monocyclic benzofused ring;

wherein R⁷ and R⁸ can be optionally substituted with one or more selected from the group consisting of alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, alkoxy, cyano, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

wherein at least one of R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

must be an optionally substituted carbon-carbon linked heterocyclic or heteroaryl;

comprising;

reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde of Formula II

with an acetophenone of Formula III

wherein R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

for Formula II and III are as defined above;

in a solvent or mixture of solvents in the presence of LiOMe.

16. The process of claim 15 wherein

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, —

C(O)NH₂, —

C(O)NHR², —

C(O)NHC(O)R², —

C(O)NHSO₂R²;

wherein at least one of R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

must be selected from the group consisting of —

C(O)NH₂, —

C(O)NHR², —

C(O)NHC(O)R², —

C(O)NHSO₂R²;

R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

are independently selected from the group consisting of hydrogen, halo, alkoxy, heteroaryloxy, heterocyclic, and heteroaryl, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heteroaryl, heterocyclic, alkoxy, oxo, carboxy, carboxyalkyl, alkoxycarbonyl, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, and heteroarylalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, heterocyclic, alkoxy, oxo, —

C(O)NH₂, and —

C(O)N(R²)₂;

wherein at least one of R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

must be an optionally substituted carbon-carbon linked heterocyclic or heteroaryl;

comprising;

reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde of Formula II

with an acetophenone of Formula III

wherein R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

for Formula II and III are as defined above;

in a solvent or mixture of solvents in the presence of LiOMe.

17. The process of claim 16 wherein

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, —

C(O)NH₂, —

C(O)NHR², —

C(O)NHC(O)R², —

C(O)NHSO₂R²;

wherein at least one of R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

must be selected from the group consisting of —

C(O)NH₂, —

C(O)NHR², —

C(O)NHC(O)R², —

C(O)NHSO₂R²;

R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

are independently selected from the group consisting of hydrogen, halo, alkoxy, heterocyclic, and heteroaryl, all of which can be optionally substituted by one or more selected from the group consisting of lower alkyl, hydroxy, hydroxyalkyl, heteroaryl, heterocyclic, alkoxy, oxo, alkoxycarbonyl, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of lower alkyl, arylalkyl, and heteroarylalkyl, wherein all may be substituted by one or more selected from the group consisting of lower alkyl, heterocyclic, alkoxy, —

C(O)NH₂, and —

C(O)N(R²)₂;

wherein at least one of R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

must be an optionally substituted carbon-carbon linked heterocyclic or heteroaryl;

comprising;

reacting a carbon-linked heteroaryl or heterocyclic substituted benzaldehyde of Formula II

with an acetophenone of Formula III

wherein R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

, and R^6β

for Formula II and III are as defined above;

in a solvent or mixture of solvents in the presence of LiOMe.

18. The process of claim 14 wherein the compound is selected from the group consisting of

4-{3E-[4-Methoxy-2-(2-morpholin-4-y 3-ethoxy)-5-thiophen-2-y3-phenyl]-acryloyl}-benzamide;

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide; and

4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzamide.

19. A process of manufacturing 4-[(2E)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid, 4-[(2Z)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid, or mixtures thereof comprising:

reacting the compound of Formula IV

with the compound of Formula V

in a solvent or mixture of solvents in the presence of LiOMe.

20. The process of claim 19 wherein said method is the method of manufacturing 4-[(2E)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid.

21. The process of claim 19 further comprising:

isolating 4-[(2E)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid;

isomerizing said 4-[(2E)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid to form 4-[(2Z)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid.

24. The process of claim 21 further comprising:

isolating 4-[(2E)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid;

isomerizing said 4-[(2E)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid to form 4-[(2Z)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid.

31. A method for the treatment or prophylaxis of an inflammatory disorder, comprising administering an effective amount of a compound of claim 24, 25 or 28.

32. The method of claim 31, wherein the disorder is arthritis.

33. The method of claim 31, wherein the disorder is rheumatoid arthritis.

34. The method of claim 31, wherein the disorder is asthma.

35. The method of claim 31, wherein the treatment is disease modifying for the treatment of rheumatoid arthritis.

36. The method of claim 31, wherein the disorder is allergic rhinitis.

37. The method of claim 31, wherein the disorder is chronic obstructive pulmonary disease.

38. The method of claim 31, wherein the disorder is atherosclerosis.

39. The method of claim 31, wherein the disorder is restinosis.

22. A process of manufacturing 4-[(2E)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid, 4-[(2Z)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid, or mixtures thereof comprising:

reacting the compound of Formula VI

with the compound of Formula V

in a solvent or mixture of solvents in the presence of LiOMe.

23. The process of claim 22 wherein said method is the method of manufacturing 4-[(2E)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid.

25. A compound selected from the group consisting of 4-[(2E)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid L-arginine salt, 4-[(2Z)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid L-arginine salt, and mixtures thereof.

26. A compound of the formula

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of 4-[(2E)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid L-arginine salt, 4-[(2Z)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid L-arginine salt, and mixtures thereof together with one or more pharmaceutically acceptable diluent or carrier.

28. A pharmaceutical composition comprising a therapeutically effective amount of 4-[(2Z)-3-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid together with one or more pharmaceutically acceptable diluent or carrier.

29. A compound selected from the group consisting of 4-[(2E)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid, 4-[(2Z)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid, and mixtures thereof.

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of 4-[(2E)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid, 4-[(2Z)-3-(5-benzofuran-2-yl-2,4-dimethoxyphenyl)-1-oxo-2-propenyl]-benzoic acid, and mixtures thereof together with one or more pharmaceutically acceptable diluent or carrier.